Decreased cytotoxicity of cis-diamminedichloroplatinum(II) by alpha-difluoromethylornithine depletion of polyamines in 9L rat brain tumor cells in vitro.
Before treatment with the cytotoxic drug cis-dichlorodiammineplatinum(II) (cis-platinum), 9L rat brain gliosarcoma cells grown in vitro were depleted of intracellular polyamines by alpha-difluoromethylornithine (DFMO; 10 mM, 48 hr), an enzyme-activated, irreversible inhibitor of the polyamine-synthetic enzyme ornithine decarboxylase. In contrast to studies that showed that the cytotoxicity of 1,3-bis (2-chloroethyl)-1-nitrosourea as measured by colony-forming efficiency is enhanced by DFMO depletion of intracellular polyamines, the cytotoxicity of cis-platinum was significantly decreased in polyamine-depleted 9L cells. At 10, 1, and 0.1% survival levels, the dose modification factors were 2.0 to 2.1. Addition of exogenous putrescine to polyamine-depleted 9L cells 24 hr before treatment with cis-platinum partially reversed this phenomenon. When 9L cells were treated either with DFMO and cis-platinum or with DFMO, putrescine, and cis-platinum for 1 hr, a time period that is too short for DFMO to affect intracellular polyamine levels, the cytotoxicity of cis-platinum was decreased, but to a significantly lesser extent than by the 48-hr DFMO pretreatment. Putrescine alone did not alter the cytotoxic effect of cis-platinum when administered either 24 or 1 hr before treatment. DFMO appears to affect cis-platinum cytotoxicity by two different mechanisms, the first mediated through polyamine depletion and the second through a direct interaction with cis-platinum.
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D002945:Cisplatin / Q000378:metabolism / Q000627:therapeutic use*; D004247:DNA / Q000378:metabolism; D000518:Eflornithine; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000494:pharmacology; D051381:Rats
D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D004247:DNA; D009952:Ornithine; D002262:Carboxy-Lyases; D002945:Cisplatin; D011700:Putrescine; D000518:Eflornithine